Colostrum (Latin: colostrum) is the first milk for mammals, which is produced by numerous mammalian species before childbirth for optimal feeding of the newborn during the first few days. It is also referred to as premilk, colostral milk, beestings or beastings (both in the case of cows) or first milk and consists of, inter alia, proteins, enzymes, vitamins, minerals, growth factors, amino acids and antibodies. By this means, the strengthening and the immune defense of the young animal or the child is supported or surrogated as a special form of loan immunity until an inherent immune system has been established after a few days to weeks.
Cow colostrum is considered to be a healthy foodstuff. There are numerous studies in relation to the effectiveness of colostrum. Colostrum is said to provide, inter alia, a certain level of protection against infectious diseases (Cesarone, et al.: Prevention of influenza episodes with colostrum compared with vaccination in healthy and high-risk cardiovascular subjects: The epidemiologic study in San Valentino: Clinical and Applied Thrombosis/Hemostasis 13(2)/2007, pp. 130-136; Tacket et al.: Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge: American Journal Tropical Medicine Hygiene 47(3)/1992, pp. 276-83; Huppertz et al.: Bovine colostrum ameliorates diarrhea in infection with diarrheogenic E. coli, Shiga toxin-producing E. coli and E. coli expressing intimin and hemolysin: J Ped Gastroenterol Nutr 29: 452-456/1999) and support wound healing and also the regeneration of damaged intestinal mucosa (Uruakpa et al.: Colostrum and its benefits: a review: Nutrition Research 22/2002, pp. 755-67). Colostrum is also used for the cotreatment of allergies, high blood pressure, diabetes mellitus and depressions. However, there is so far a lack of evidence for the effectiveness of use in these indications.
Cholecalciferol, vitamin D3, is the vitamin D which occurs physiologically in all nonplant eukaryotes. It is formed in the body in the skin from 7-dehydrocholesterol with the aid of ultraviolet light (UVB).
In food, it occurs especially in oily fish (in contrast to the group of varieties relatively low in fat that are called whitefish in fishery, such as cod or haddock, oily fish refers to edible fish, in the muscle tissue of which fat exceeds a proportion of about two percent; depending on the species, said proportion can be over 30 percent. Examples of known species are herring, sprat, sardine and anchovy, salmon, mackerel, tuna, eel and carp. Because of their content of omega-3 fatty acids, sea-living oily fish are considered to be nutritionally and physiologically valuable) or is added as food supplement to foodstuffs. It acts as a prohormone in the body and is converted to the hormone calcitriol via an intermediate stage.
Calcitriol, also called 1α,25-dihydroxycholecalciferol (1α,25-dihydroxyvitamin D3) or 1,25(OH)2D3 for short, is a highly potent secosteroid with structural similarity to the steroid hormones. It is—as explained—the physiologically active form of the prohormone vitamin D3. It is hydroxylated from 25-hydroxyvitamin D3 by means of the 1α-hydroxylase especially in the kidneys, but also in other tissues, or prescribed as medicament in rare cases. Calcitriol is bound to an intracellular receptor protein, the vitamin D receptor (VDR), and transported into the cell nucleus. There, the vitamin/receptor complex associates to the DNA and alters the transcription of various hormone-sensitive genes, ultimately leading to changes in protein synthesis with corresponding biological effects.
Vitamin D has, inter alia, an important role to play in blood calcium level regulation and in bone formation. In the medium term, a deficiency of vitamin D leads to various diseases, for example rickets or osteomalacia.
Lactoferrin (more precisely: lactotransferrin; from the Latin lacteus (milk), ferrum (iron) and transferre (to carry across)) is a protein which occurs in mammals and has multifunctional enzyme activities.
Lactoferrin belongs to the protein family of transferrins. Transferrins do not occur only in mammals; homologous genes are also found in other vertebrates and invertebrates.
Lactoferrin can be found in many body fluids of mammals, in the milk, tears, saliva, sweat, vaginal secretion, seminal plasma, nasal and bronchial secretion thereof and also other secretions thereof. In addition, it is located in white blood cells.
Lactoferrin has both antiviral (Harmsen, Martin C. et al.: Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. Journal of Infectious Diseases, Vol. 172, No. 2, 1995, pages 380-388) and antimicrobial (Park, Ji-Hye et al.: An antimicrobial protein, lactoferrin exists in the sweat: proteomic analysis of sweat. Experimental Dermatology, Vol. 20, No. 4, 2011, pages 369-371) properties. It acts not only as a peptidase (cleavage of peptides), which is why it is assigned to the group of the serine proteases, but also as an iron-binding protein—similar to transferrin—and additionally exhibits deoxyribonuclease and ribonuclease activities, whereby it is classed with the nucleases (EC 3.1.21.1). In addition, it is a strong inhibitor for tryptase.
One liter of cow's milk contains approx. 0.1 g of lactoferrin. It is saturated with iron only to a small proportion and can bind more than five times its original iron load.
Industrially, it is isolated from milk and whey. It is used in baby food and sports food, and also in cosmetics, chewing gums and functional foods.
The organism uses lactoferrin, inter alia, to deplete bacteria of iron, which is necessary for life. Since bacteria have an essential dependence on iron, the depletion of iron has an antibacterial effect. As a protease, lactoferrin is capable of destroying two or more proteins of the pathogen Haemophilus influenzae that are important for colonization. In addition, it compromises the type III secretion system in Shigella and pathogenic Escherichia coli. Released by leukocytes, it is thus also part of the immune system.
Colostrum or colostrum preparations are supplied commercially in a variety of ways and processed forms. For example, colostrum preparations are commercially available as liquid, in capsule form, as Colobons or as skin balm.
One supplier of colostrum preparations is the company Dr. Wolz Zell GmbH, Marienthaler Strasse 3, 65366 Geisenheim (www.wolz.de), which supplies a colostrum preparation in powder form under the brand name Lactobin® N.
In the case of said Lactobin® N or its bioequivalent precursor preparation Lactobin® Biotest, it has been known for some time that the antibody specifications which occur in the preparations act against bacterial lipopolysaccharides.
These findings of the use of Lactobin® N led to preclinical and clinical studies which have been described in two review publications by W. Struff and G. Sprotte (W. G. Struff and G. Sprotte: Bovine colostrum as a biologic in clinical medicine: a review. International Journal of Clinical Pharmacology and Therapeutics, Vol. 45—No. 4/2007 (193-202); W. G. Struff and G. Sprotte: Bovine colostrum as a biologic in clinical medicine: a review—Part II: International Journal of Clinical Pharmacology and Therapeutics, Vol. 46—No. 5/2008 (211-225).
On the basis of an incidental finding by G. Sprotte with regard to disturbed apoptosis functions of mononuclear cells in the blood of patients suffering from chronically recurring pain, patients were successfully treated during and also beyond their typical episode of pain, whereby the causal relationship between development of pain and elimination of pain by means of Lactobin® N was recognized as related to the apoptosis function normalized by the administration of the preparation (A. M. Waaga-Gasser et al.: Oral immunoglobulin induces mononuclear cell apoptosis in patients suffering from idiopathic chronic pain syndrome: results from a pilot study. International Journal of Clinical Pharmacology and Therapeutics, Vol. 47—No. 7/2009 (421-433).
Proinflammatory cytokines in the examined peripheral blood were noticeably elevated during an episode of pain, whereas anti-inflammatory cytokine profiles were measured as lowered. Treatment with Lactobin® N led to the reversal of these profiles, with the simultaneous reoccurrence of pain in the case of a deliberately effected drug holiday. The additionally determined serum level of insulin-like growth factor I (IGF I), too, was found to be significantly elevated in the treatment-free phase and dropped to the normal level with Lactobin® N. This phenomenon too is unambiguously seen by the investigators in connection with apoptosis dysfunction and the development of pain and the relief of pain with Lactobin® N. A similar finding of an extraintestinal remote effect of the colostrum preparation on other body compartments had been observed for the first time in a clinical study with the precursor preparation (Lactobin® Biotest); in this respect, there was a significant lowering of the peripherally elevated LPS level (in comparison with the placebo group) in serum when treating abdominal surgery patients (Edwin Bölke et al.: PREOPERATIVE ORAL APPLICATION OF IMMUNOGLOBULIN-ENRICHED COLOSTRUM MILK AND MEDIATOR RESPONSE DURING ABDOMINAL SURGERY. SHOCK, Vol. 17, No. 1, pp. 9-12, 2002).
Furthermore, in many patients with diverse tumor entities, there is a disturbance in the apoptosis in immunocompetent cells, representing a significant underlying problem in the case of a progressive tumor disease. The intensified downfall of immune cells is maintained by a dysregulation of LPS-triggered, chronically elevated inflammatory processes (chronic inflammation). In relation to this, relevant pathophysiological findings have only recently become available and have been substantiated especially by the research into toll-like receptors (TLR). In this connection, reference is made to the preclinical experimental results from Fitzal et al. (Florian Fitzal et al.: Immunoglobulin Enriched Colostral Milk Reduces Gut-Derived Endotoxemia in a Rat Hemorrhage Model. European Journal of Trauma, 2001, pp. 257-263) and the already mentioned results of the clinical phase II study with Lactobin® N (Edwin Bölke et al.: PREOPERATIVE ORAL APPLICATION OF IMMUNOGLOBULIN-ENRICHED COLOSTRUM MILK AND MEDIATOR RESPONSE DURING ABDOMINAL SURGERY. SHOCK, Vol. 17, No. 1, pp. 9-12, 2002). These findings suggest that the colostrum preparation, as a result of intraenteral LPS neutralization, reduces the gastrointestinal crossing of the bacterial toxin from the intestinal surface into central body compartments. Although denaturation processes and a partial proteolytic degradation of the bovine protein molecules take place in the gastrointestinal tract, at least 20% of the ingested amount of the bovine IgG reach the ileocecal valve in presumably active form (N. ROOS et al.: 15N-Labeled Immunoglobulins from Bovine Colostrum Are Partially Resistant to Digestion in Human Intestine. The Journal of Nutrition, 1995, pp. 1238-1244; R. Lissner et al.: Antibody reactivity and fecal recovery of bovine immunoglobulins following oral administration of a colostrum concentrate from cows (Lactobin) to healthy volunteers. International Journal of Clinical Pharmacology and Therapeutics, Vol. 36, No. 5—1998 (239-245)).
Furthermore, various epidemiological studies have yielded indications of a correlation between the size of the calcitriol plasma level of patients and the incidence thereof for various cancers (Stubbins R E et al. 2012. Using components of the vitamin D pathway to prevent and treat cancer. Nutrition Reviews 70: 721-729; Manson J E. 2011. Vitamin D and Prevention of Cancer—Ready for Prime Time?. NEJM 364(15): 1385-87; Pietschmann P. et al. 2003. Bedeutung von Vitamin D im Immunsystem [Significance of vitamin D in the immune system]. J Mineral Stoffwechs 10(3): 13-15; BMJ Research. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study BMI/OnlineFirst/bmj.com).
Past investigations indicate an influence of vitamin D receptor-mediated intracellular mechanisms on the crucial deregulated Wnt/β-catenin signaling pathways in tumor cells. Furthermore, vitamin D3 appears, as a result of cooperation with other regulatory signaling pathaways via the human vitamin D receptor as a crucial nuclear receptor in the (tumor) cell, to develop immunoregulatory and antitumorigenic effects and also antimicrobial and detoxifying effects (Haussler M R et al. Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention. Nutritional Reviews 2008; 66: 98-112).
In addition, it has recently become clear that there is a distinctly lowered vitamin D receptor density in tumor cells. The reasons for this continue to remain very largely unknown; however, they make therapeutic strategies for elevating the vitamin D level and its receptor density on tumor cells all the more significant.
From the patent literature, some documents describing the use of colostrum or a colostrum preparation—or individual biologically active consitituents therefrom—are known.
For example, EP 0917467 A1 describes the treatment of inflammatory intestinal diseases using colostrum. A reference to the addition of further active ingredients as combination therapy or the treatment of specific diseases cannot be found in the document.
EP 2121002 A1 describes, inter alia, the use of lactoferrin or lactoferrin/metal ions—specifically as a result of later treatment to give 100% iron-saturated lactoferrin—and also at least one antitumor foodstuff factor such as, for example, soy protein for the treatment of cancer. The use of the colostrum or a colostrum preparation—having all the biologically active constituents—without the necessary iron saturation and also the addition of further active ingredients as combination therapy is not described.